Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. Hyperglycemia has been recognized as a major risk factor in the development and progression of diabetic nephropathy. Hyperglycemia-induced increase in proximal tubule (PT) Na+ retention has been shown in diabetic patients and in animal models of diabetes. This enhanced Na+ reabsorption may play a role in the development of hypertension, which is an additional contributing factor in the development of diabetic nephropathy and the end stage renal disease. A role for a PT sodium-glucose cotransporter (SGLT) in hyperglycemia-induced increased sodium retention has been suggested but this transporter has not yet been identified. Kidney expresses SGLT1 and SGLT2 on the apical side of the PT cells. These proteins play crucial roles in sodium-dependent uptake of glucose from the glomerular filtrate. SGLT3 mRNA has been found in the human kidney carcinoma cells and in the pig kidney. When over-expressed in Xenopus oocytes, human SGLT3 did not transport glucose but in response to glucose, it mediated inward flux of sodium. Mouse has two genes encoding SGLT3a and 3b and we have shown that their mRNAs were expressed in the kidney and in the cultured kidney cells from mouse. We also showed while mRNA levels of SGLT3s in cultured mouse primary kidney cells exposed to cadmium were several folds higher than in their levels in untreated cells, the sodium-dependent uptake of glucose in Cd-treated cells had decreased supporting that SGLT3 is not a glucose transporter. Based on the above and additional preliminary studies with the potent agonist of SGLT3, deoxynojirimycin (DNJ), we hypothesize that kidney SGLT3 serves as a novel glucose-stimulated Na+ transporter in the PT that may play role in hyperglycemia-induced Na+ retention in diabetes. To test our hypothesis, we propose: (1) To localize the SGLT3 protein in human and mouse kidneys, (2) To determine the role of SGLT3 in glucose-mediated Na+ uptake in PT cells in vitro, (3) To determine the role of SGLT3 in hyperglycemia-mediated PT Na+ reabsorption in vivo. The proposed in vitro and in vivo studies are designed to investigate the role of SGLT3 as a novel glucose-stimulated Na+ transporter that may play role in the enhanced Na+ reabsorption in diabetes. PUBLIC HEALTH RELEVANCE: One of the major adverse health effects of diabetes is damage to the kidneys. Increased kidney salt reabsorption in diabetes may play a role in the development of high blood pressure, which in turn can cause damage to the kidneys. The mechanism of diabetes-induced increased salt reabsorption is not known. We have evidence that a novel sodium transporter may be a mediator. The goal of this study is to show that human kidneys express this protein and also to show that glucose stimulates sodium uptake by this transporter. This study is designed to identify the mechanism for the enhanced salt retention in diabetes.